Despite the success of highly active anti-retroviral therapy in controlling virus replication in HIV-1 positive individuals, problems such as drug resistance and side effects often compromise the effectiveness of anti-HIV- 1 drug. Therefore, new anti-HIV agents with novel mechanisms of action are needed. In an effort to identify novel anti-HIV-1 agents, we have developed potent betulinic acid (BA) derivatives that inhibit HIV-1 maturation. These compounds are structurally and mechanistically novel when compared to the drugs currently used for AIDS therapy. Their potentials for treatment of AIDS are currently being evaluated under different stages of preclinical or clinical studies. Bevirimat is at the most advanced stage of drug development among the anti- HIV-1 BA derivatives. Although bevirimat is a potent HIV-1 maturation inhibitor, results of phase II clinical trials indicate that it is less effective in a subset (30-40%) of HIV-1 positive individuals. Therefore, bevirimat analogs that can overcome this high baseline drug resistance are expected to have great potential to be developed into anti-HIV-1 drugs. The objective of this study is to synthesize bevirimat analogs that overcome the high baseline drug resistance. We have previously identified the C3 side chain as the anti-HIV-1 maturation pharmacophore of bevirimat. We hypothesize that suitable modifications of the pharmacophore will create a new class of bevirimat analogs that are effective against the drug resistant viruses. We plan to test this hypothesis and accomplish the objective of this study with the following Specific Aims: (1) to synthesize BA derivatives with optimized pharmacophores. (2) To identify new terpenoid scaffolds and auxiliary groups for the synthesis of new anti-maturation inhibitors against the drug resistant viruses. (3) To determine the drug binding site and mechanism of action of the anti-HIV-1 maturation BA derivatives. Aside from the high baseline drug resistance to bevirimat, results from clinical trials have been promising. The proposed study is expected to overcome this drug resistance and, as a result, will have a high impact on developing a class of novel anti-HIV-1 maturation inhibitors for AIDS therapy. PUBLIC HEALTH RELEVANCE: The goal of the proposed study is to develop potent anti-HIV-1 agents that can overcome the drug resistance associated with the HIV-1 maturation inhibitor bevirimat. Aside from the high baseline drug resistance to bevirimat, results of clinical trials have been very successful. The proposed study is expected to overcome this drug resistance and, as a result, will have high impact on developing anti-HIV-1 maturation inhibitors for AIDS therapy.